University of Dundee

'Regulation of inflammation by TPL-2 kinase'

Event Date: 
Monday, July 17, 2017 - 12:30
Event Location: 
MSI Small Lecture Theatre
Professor Simon Arthur
Event Speaker: 
Dr Steve Ley
Francis Crick Institute - Mill Hill Laboratory
Event Type: 
Steve Ley, Ph.D. is a Senior Group Leader at the Francis Crick Institute – Mill Hill Laboratory (previously the MRC National Institute for Medical Research), where he has run an independent group since 1992. He received his Ph.D. at the University of Cambridge in 1987, subsequently carrying out his post-doctoral training at the Dana-Farber Cancer Institute, Boston (1987-1990) and the Imperial Cancer Research Fund, London (1990-1992).
Steve’s laboratory studies signal transduction pathways involved in innate and adaptive immune responses, with a particular focus on MAP kinase signaling. His laboratory has made fundamental contributions to the understanding of the activation and function of TPL-2, a MAP 3-kinase that mediates ERK1/2 MAP kinase activation by TLRs in macrophages during innate immune responses. His group has also established the physiological importance of the IKK signaling pathway that induces proteolysis of NF-κB1 p105 in regulating NF-κB activation in T and B cells in adaptive immune responses. In a new area of research, Steve’s group have started to investigate how the adaptor protein CARD14 activates NF-κB to trigger inflammation in the skin. Mutations in the gene encoding CARD14 lead to a high risk of developing psoriasis and psoriatic arthritis.
Selected References
TLR and TNFR1 activation of the MKK3/MKK6-p38α axis in macrophages is mediated by TPL-2 kinase. (2016) Pattison, M. J., Mitchell, O., Flynn, H. R., Chen, C.-S., Yang, H.-Y., Ben-Addi, A., Boeing, S., Snijders, A. P. & Ley S. C. Biochem J. 473: 2845-2861.
Psoriasis mutations disrupt CARD14 autoinhibition promoting BCL10-MALT1-dependent NF-κB activation. (2016) Howes, A., O’Sullivan, P. A., Breyer, F., Ghose, A., Cao, L., Krappmann, D., Bowcock, A. M. & Ley, S. C. Biochem. J. 473: 1759 – 1768.
BAFF activation of the ERK5 MAP kinase pathway regulates B cell survival. (2015) Jacque, E., Schweighoffer, E., Tybulewicz, V. L. & Ley, S. C. J. Exp. Med212: 883-92.
IKK-induced NF-κB1 p105 proteolysis is critical for B cell antibody responses to T cell-dependent antigen. (2014) Jacque, E., Schweighoffer, E., Visekruna, A., Papoutsopoulou, S., Janzen, J., Zillwood, R., Tarlinton, D. M., Tybulewicz, V. L. &Ley, S. C. J. Exp. Med. 211: 2085-101.
IκB kinase-induced interaction of TPL-2 with 14-3-3 is essential for TLR activation of ERK 1 and 2 MAP kinases. (2014) Ben-Addi, A., Mambole-Dema, A., Brender, C., Martin, S., Janzen, J., Kjær, Smerdon, S. J. & Ley, S. C. Proc. Natl. Acad. Sci. USA, 111: E2394 – 2403.
Regulation of experimental autoimmune encephalomyelitis by TPL-2 kinase. (2014) Sriskantharajah, S., Gückel, E., Tsakiri, N., Kierdorf, K., Brender, C., Ben-Addi, A., Veldhoen, M., Tsichlis, P. N., Stockinger, B., O’Garra, A., Prinz, M., Kollias, G. & Ley, S. C. J. Immunol. 192: 3518 – 3529.
Roget, K., Ben-Addi, A., Mambole-Dema, A., Gantke, T., Janzen, J., Yang, H.-T., Shpiro, N., Morrice, N., Abbott, D. and LeySC. (2012) IKK2 regulates TPL-2 activation of ERK-1/2 MAP kinases by direct phosphorylation of TPL-2 serine 400.Mol. Cell. Biol. 32: 4684 – 4690.
Yang, H.T., Papoutsopoulou, M., Belich, M.P., Brender, C., Janzen, J., Gantke, T., Handley, M. and LeyS.C. (2012) Coordinate regulation of TPL-2 and NF-κB signaling in macrophages by NF-kB1 p105. Mol. Cell. Biol. 32: 3438 – 3451.